Department of Organ Transplantation, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
Department of Kidney Transplantation, The Affiliated Hospital of Qingdao University, Qingdao, China.
Pharmacol Res Perspect. 2023 Jun;11(3):e01081. doi: 10.1002/prp2.1081.
Tacrolimus is an independent risk factor for new-onset diabetes after transplantation (NODAT). This study aimed to identify the mechanisms underlying tacrolimus-induced NODAT. About 80 kidney-transplant patients receiving tacrolimus were divided into NODAT and non-NODAT groups after 1 year. Binary logistic regression was used to identify risk factors for NODAT. Insulin resistance indices were estimated using the homeostasis model assessment. The blood levels of 13 adipocytokines were measured 1 week after transplantation. A tacrolimus-induced diabetes mouse model was used to reveal the underlying mechanisms. The cumulative NODAT incidence was 12.7% at 1 year (median, 6 months; range, 3-12 months). Tacrolimus trough levels ≥10 ng/mL during the first 3 months (odds ratio: 2.54, p = .012) were related to NODAT. Insulin resistance indices were higher in NODAT patients than in non-NODAT patients at 3, 6, and 12 months. Monocyte chemoattractant protein (MCP)-1 was overexpressed in blood in NODAT patients. In the animal experiments, postprandial blood glucose and insulin levels, insulin pathway protein levels in adipose tissue, MCP-1 expression in blood and adipose tissue, and number of macrophages in adipose tissue were markedly higher in tacrolimus-treated mice than in control mice, and these increases were dose-dependent. The expression of endoplasmic reticulum (ER) stress proteins in adipose tissue was increased in a tacrolimus dose-dependent manner. In conclusion, tacrolimus-induced insulin resistance. Tacrolimus trough levels ≥10 ng/mL during the first 3 postoperative months were an independent risk factor for NODAT. ER stress and MCP-1 underlie tacrolimus-induced diabetes.
他克莫司是移植后新发糖尿病（NODAT）的独立危险因素。本研究旨在确定他克莫司诱导 NODAT 的机制。大约 80 名接受他克莫司治疗的肾移植患者在 1 年后分为 NODAT 和非 NODAT 组。采用二项逻辑回归分析 NODAT 的危险因素。采用稳态模型评估法估计胰岛素抵抗指数。移植后 1 周测量了 13 种脂肪细胞因子的血水平。使用他克莫司诱导的糖尿病小鼠模型揭示潜在机制。1 年后 NODAT 的累积发生率为 12.7%（中位数，6 个月；范围，3-12 个月）。在最初的 3 个月内，他克莫司谷浓度≥10ng/mL（优势比：2.54，p=0.012）与 NODAT 相关。在 3、6 和 12 个月时，NODAT 患者的胰岛素抵抗指数高于非 NODAT 患者。NODAT 患者的血液中单核细胞趋化蛋白-1（MCP-1）表达过度。在动物实验中，与对照组相比，他克莫司治疗的小鼠的餐后血糖和胰岛素水平、脂肪组织胰岛素通路蛋白水平、血液和脂肪组织 MCP-1 表达以及脂肪组织中的巨噬细胞数量明显升高，且呈剂量依赖性。脂肪组织中内质网（ER）应激蛋白的表达也呈他克莫司剂量依赖性增加。总之，他克莫司诱导胰岛素抵抗。术后前 3 个月他克莫司谷浓度≥10ng/mL 是 NODAT 的独立危险因素。内质网应激和 MCP-1 是他克莫司诱导糖尿病的基础。
